Keywords

Abstract

Introduction and objectives. Numerous clinical and epidemiological studies have highlighted the fact that metabolic syndrome is an important precursor of cardiovascular disease. Metabolic syndrome is generally associated with type-2 diabetes, and few data exist on its occurrence in type-1 diabetes. The aims of this study were to determine the prevalence of metabolic syndrome in patients with type-1 diabetes and to identify associated factors. Methods. This cross-sectional study included consecutive patients aged over 18 years with autoimmune type-1 diabetes of more than 6 months duration who were treated during 2008 at the Outpatient Endocrinology Clinic of the Hospital del Mar, Barcelona, Spain. The presence of metabolic syndrome was determined using the modified criteria proposed by the National Cholesterol Education Program-Adult Treatment Panel III. Results. Overall, 31.9% (95% confidence interval [CI], 22.3%-41.5%) of patients with type-1 diabetes had metabolic syndrome. The following factors were significantly and independently associated with the presence of metabolic syndrome in patients with type-1 diabetes: age (odds ratio [OR]=1.09; 95% CI, 1.029-1.154), body mass index (OR=1.389; 95% CI, 1.134-1.702) and glycosylated hemoglobin level (OR=1.745; 95% CI, 1.081-2.815). In addition, there was a direct relationship between the number of components of metabolic syndrome present and prevalence of microangiopathy, which reached 100% in patients who satisfied all diagnostic criteria. Conclusions. Metabolic syndrome was common in patients with type-1 diabetes and was associated with microvascular complications.

Article

INTRODUCTION

Traditionally, persons with type-1 diabetes
mellitus (DM1) usually have a normal or low weight
and a tendency for the late development of arterial hypertension and dyslipidemia. Until a few years ago,
the main causes of death in persons with DM1 were
those derived from microvascular complications,
particularly kidney disease.1 Although therapeutic
advances for the treatment of DM1 and its main
associated cardiovascular risk factors have led to
significant reductions in the rates of death and
microvascular complications,2-5 no similar trend has
been seen with cardiovascular disease.6

Though DM1 involves the immune destruction
of the pancreatic beta cells and usually presents at
an early age, affected persons are not exempt from
developing insulin resistance at some earlier stage
in the course of the disease,7-9 which is known as "double diabetes." This phenomenon usually appears
in patients with a family history of type 2 diabetes
mellitus (DM2) and is associated with a greater body
mass index, greater insulin requirements and worse
metabolic control.10 As well as the insulin resistance,
other factors can explain why cardiovascular disease
is the leading cause of death in these patients, such
as the chronic complications of DM1, like kidney
disease,11 and the earlier age of onset of the disease,
with the resulting longer period of exposure to the
main cardiovascular risk factors, together with a poor
control of these risk factors.12,13 As a consequence, the phenotypic characteristics and cardiovascular
risk profile of patients with DM1 have become more
similar to those of DM2 over recent years.

Since the first description of the metabolic
syndrome, by Reaven in 1988,14 numerous studies
have established its association with a high
prevalence of cardiovascular disease and death.15-18 About 10.2% of the Spanish working population
have the metabolic syndrome, and this figure
rises to 58.4% in persons with DM2 and 50.4%
in persons with impaired fasting glucose.19 Most studies have been undertaken in patients aged 40
years or over, many with DM2 or impaired fasting
glucose, with very few data available for patients
with DM1. Given the lack of relevant studies in
our setting, we examined the prevalence of the
metabolic syndrome in patients with DM1 and its
possible related factors.

METHODS

Patients

We undertook a cross-sectional study of patients
with DM1 seen consecutively between January and
December 2008 at the Outpatient Endocrinology
Clinic of the Hospital del Mar in Barcelona,
Spain. DM1 was considered to be autoimmune
when it fulfilled the diagnostic criteria for diabetes
mellitus20 together with positive tests for anti-GAD/65 Ks or anti-IA2 antibodies at the start
and a concentration of free C-peptide <1.1 ng/mL
6 min after intravenous administration of 1 mg of
glucagon. Non-Caucasian patients were excluded,
as were patients with variations in the concentration
of glycosylated hemoglobin >1% at 3 bimonthly
determinations, pregnant women, patients who had
an excessive consumption of alcohol, patients with
chronic end-stage kidney failure, kidney transplant
recipients or those on hemodialysis. No patient was
being treated with insulin sensitizing drugs, such as
thiazolidinediones or metformin. The study protocol,
approved by the hospital Ethics Committee, included
a physical examination and a blood test. All the
participants were aged 18 years or over and had had
diabetes for longer than 6 months.

Data were recorded for each patient on age,
sex, time since the diagnosis of diabetes, history
of major cardiovascular events (acute myocardial
infarction, coronary revascularization procedures,
angioplasty, stroke, transient ischemic attack, and
peripheral vascular disease, defined as the presence
of intermittent claudication or amputation), as
well as the presence of chronic microangiopathic
complications of the diabetes (microalbuminuria
or macroalbuminuria, retinopathy, peripheral or
autonomic neuropathy). The presence of complications
was evaluated by an expert diabetologist (JJC), except for
retinopathy, which was assessed by an ophthalmologist.
The criteria of the American Diabetes Association
were used for the clinical diagnosis of complications,20 and the insulin requirements were estimated in units
per kilogram of body weight (U/kg/d). The physical
examination included measurements of weight, height
and abdominal waist circumference, as well as the
blood pressure using standardized methods.

The renal status was classified from the urinary
albumin excretion (UAE): a) absence of kidney
disease was defined as normoalbuminuria
(UAE<30 mg/24 h); b) incipient kidney disease as
microalbuminuria (UAE 30-300 mg/24 h); and c)
established kidney disease as macroalbuminuria
(UAE>300 mg/24 h). The UAE was expressed as
the mean of three 24 h urine samples taken at the
patient's home during a period of normal activity on
2 separate occasions, at least 1 month apart.

Measurements

All the patients included in the study had venous
blood drawn after a 12 h fast. Measurements were
made of the concentrations of total cholesterol and
triglycerides using enzymatic methods in a Cobas
Mira automatic analyzer (Baxter Diagnostics
AG, Düdingen, Switzerland) and separation of
high density lipoprotein cholesterol (HDL-C) by
phosphotungstic acid and magnesium chloride
precipitation. Blood glucose was measured by the
glucose oxidase method. Glycosylated hemoglobin
was quantified by chromatography (Biosystem,
Barcelona, Spain) and the urinary excretion of
albumin by nefelometry (intra-assay coefficient
of variation, 2%). Free C-peptide was determined
by radioimmunoassay 6 min after the intravenous
administration of 1 mg of glucagon, in a fasting
state and with a baseline glycemia <180 mg/dL to
avoid beta cell glucotoxicity, at least 1 month after
starting insulin therapy. The prior insulin dose was
administered the night before.

Criteria for the Metabolic Syndrome

In accordance with the modified criteria of the
National Cholesterol Education Program -Adult
Treatment Panel III (NCEP-ATP III),21 the metabolic syndrome was diagnosed if the patient
had 3 or more of the following conditions: fasting
plasma glucose ≥100 mg/dL or treatment with
glucose lowering dugs, arterial blood pressure
≥130/85 mmHg or antihypertensive medication,
fasting plasma triglycerides ≥150 mg/dL (1.7
mmol/L) or drug treatment for hypertriglyceridemia,
HDL-C <40 mg/dL (1.03 mmol/L) in men and <50
mg/dL (1.3 mmol/L) in women or drug therapy to
raise the HDL-C concentration, and an abdominal
waist circumference ≥102 cm in men and ≥88 cm in
women.

Statistical Analysis

For an alpha risk of .05 and precision of ±10%
in a bilateral contrast for an estimated 40% rate of
the metabolic syndrome and assuming a population
of 100 000, we required a random sample of 93
persons.

The Student t test was used to compare means
and the χ2 test for categorical variables, as well as
the Mann-Whitney U test for variables that did
not follow a normal distribution, and Pearson's
correlation coefficient to establish relations between
quantitative variables. To evaluate the factors
associated with the presence of the metabolic
syndrome (dependent variable), a multiple logistic
regression model was applied that included as independent variables those which had a P<.1 in
the univariate analysis. The results were analyzed
using the statistical program SPSS, version 12.0 for
Windows.

RESULTS

Of the 165 patients seen at the Outpatient
Endocrinology Clinic during 2008, 56 were excluded
due to lack of confirmation of the diagnosis of
autoimmune DM1, variations in the glycosylated
hemoglobin concentration, excessive consumption
of alcohol or end-stage renal failure. Of the 109
patients eligible, 91 (83.5%) completed the study
protocol and composed the definitive sample. The
age (mean [standard deviation]) of the patients was 39.7 (13.2) years; 53 were men and 38 women, with
a mean duration of DM1 of 16.7 (12.9) years and
a mean glycosylated hemoglobin concentration of 7.29% (1.4%).

All the patients fulfilled the criterion of high fasting plasma glucose; 57 (62.6%) fulfilled 2 or
more criteria; 29 (31.9%), 3 or more; 11 (12.1%), 4
or more; and 2 (2.2%) fulfilled all the criteria for the
metabolic syndrome. Thus, 29 patients (17 men, 12
women) had the metabolic syndrome according to
the NCEP-ATP III modified criteria,21 giving an
overall prevalence of 31.9% (95% confidence interval
[CI], 22.3-41.5). Table 1 shows the prevalence of each
of the components of the metabolic syndrome in the
whole group of patients with DM1.

The most frequent criterion among the patients
with the metabolic syndrome, besides glycemia, was
the HDL-C concentration, present in 93.1% of the
cases, followed by hypertension (72.4%), abdominal
obesity (58.6%) and hypertriglyceridemia (20.7%).
These percentages contrast with those seen in the
patients with DM1 but without the metabolic
syndrome (Figure 1).

The patients with DM1 and the metabolic syndrome
were older and had longer duration of diabetes,
higher body mass index and a greater prevalence
of overweight than those DM1 patients without
the metabolic syndrome (Table 2). No differences
were found in the percentage of macroangiopathic
complications. However, the patients with DM1
and the metabolic syndrome had a significantly
higher prevalence of microangiopathic complications
(retinopathy, neuropathy and nephropathy) than the
DM1 patients without the metabolic syndrome. In
addition, a direct relation was detected between the
number of components of the metabolic syndrome and
the prevalence of microangiopathy, reaching 100% in those patients who had all the diagnostic criteria for
the metabolic syndrome (Figure 2). On the other hand,
the daily insulin requirements were similar in patients
with and without the metabolic syndrome (0.69 [0.2] vs 0.72 [0.3] U/kg/d).

Figure 2. Prevalence of microvascular
complications according to the number of
components of the metabolic syndrome.

In the multiple logistic regression analysis, age, body mass index and glycosylated hemoglobin retained
a significant and independent association with the
presence of the metabolic syndrome (Table 3).

DISCUSSION

This study found a prevalence of the metabolic
syndrome in patients with DM1 of 31.9% (31.5% in women and 32% in men). Studies of Americans
with DM1 found rates ranging from 21% to 8%,
depending on the diagnostic criteria used.22 In Europe, studies such as the FinnDiane study23 found a prevalence of the metabolic syndrome of 39%
according to the NCEP-ATP III criteria. Similar
data have been reported for the Mediterranean area,
where a prevalence of 40.8% was found using the
same criteria.24

Of all the components of the metabolic
syndrome (independently of glycemia, which was
present in all the subjects), the most frequent was
hypoalphalipoproteinemia. Persons with DM1 in our
area have been found to have low levels of HDL-C
(<35 mg/dL in men and <45 mg/dL in women),
around 12% in patients with good metabolic control
and 20% in those with poor control.25

Of each 3 patients with DM1 and the metabolic
syndrome, 2 had abdominal obesity, defined from
the abdominal waist circumference. These data
agree with those found during the follow-up of the
DCCT cohort,26 in which the average weight gain
after insulin therapy was 14 kg. Importantly, in the present study no differences were found in the
daily insulin requirements between the patients with
and without abdominal obesity (0.69 [0.15] vs 0.72 [0.34] U/kg/d), which indicates that factors such as
dietary habits, exercise or a family history must be
intervening in the development of visceral obesity.

Concerning the repercussion of the metabolic
syndrome on chronic complications, the proportion
of patients with microangiopathy was clearly greater
among those who had this complication. This
confirms the results reported in other European
series, which have found prevalence rates of the
metabolic syndrome reaching 62% in patients with
macroalbuminuria, and an odds ratio of 3.75 (95%
CI, 2.89-4.85) for diabetic nephropathy in the case
of the metabolic syndrome.23 In the present study,
the proportion of patients with microangiopathy
rose in parallel with the number of components of
the metabolic syndrome, reaching 100% in those
persons who had all 5 diagnostic criteria.

Studies in a large number of patients with a
long-term follow-up have also shown the relation
between insulin resistance, the metabolic syndrome
and macroangiopathy,12,27,28 an association that was
not found in our study. The low number of cases in
both groups, the mean age of the patients, the good
metabolic control and the relatively short mean
duration of the diabetes (16.7 years) may all have
contributed to the lack of significant differences in
macrovascular complications. In addition, most of
these patients were diagnosed after publication of
the DCCT study results, and they have therefore
followed intensive insulin treatment since their
diagnosis, which has been shown to reduce the
incidence of severe cardiovascular events by 42%
over 20 years.29 Finally, strict criteria have been
published for the diagnosis of autoimmune DM1,
which exclude young patients with DM2, in whom the prevalence of macroangiopathy on diagnosis
may reach 20% given the delay between the onset
of the hyperglycemia and the diagnosis,30 due to the close association between DM2, the metabolic
syndrome and cardiovascular disease.31

The multiple logistic regression model showed
that the degree of blood glucose control, evaluated
from the glycosylated hemoglobin, was the most
influential variable in the development of the
metabolic syndrome, followed by the body mass
index and age. Earlier studies found no influence of
metabolic control,11 though it is worth noting that
the glycosylated hemoglobin in these studies was
above 10%, almost 3% higher than in the present
study.

Limitations

The limitations of this study derive from its cross-sectional design. Thus, we should recall not only
the possible variations over time in the parameters
studied but also that the findings only refer to
associations, and do not imply causality. The sample
size was the result of applying strict criteria for
the diagnosis of autoimmune DM1 and excluding
patients with a short disease evolution in order to
avoid the effects of insulinopenia on the glycosylated
hemoglobin and the anthropometric variables. In
any event, the baseline characteristics of the patients
included in the study were those of the population
with DM1 in our setting.32

CONCLUSIONS

The metabolic syndrome is common in patients
with DM1, and was present in one third of the patients
with diabetes mellitus in our area, particularly the
patients who were older, had a higher body mass
index and worse metabolic control. The presence
of the metabolic syndrome in this group of patients
was associated with microvascular complications.